Method and apparatus for administration of contrast agents for use in magnetic resonance arteriography

ABSTRACT

The present invention is a method and apparatus for providing preferential enhancement of an artery of interest relative to adjacent veins and background tissue. The method and apparatus adapts the timing of a maximum or substantially elevated rate of infusion to correlate with the collection of image data corresponding to the center of k-space. The technique and apparatus temporally correlates the timing of a maximum or substantially elevated rate of infusion and the mapping of k-space according to the location of the artery of interest, the size of the artery of interest, the physical condition of the patient, the time delay due to the configuration of the contrast agent delivery system, and/or the type of pulse sequence employed by the imaging apparatus. Adapting the timing of a maximum or substantially elevated rate of infusion to correlate with the collection of image data corresponding to the center of k-space provides a period of a maximum or substantially elevated contrast concentration in the artery of interest relative to adjacent veins during collection of at least a portion of the image data corresponding to the center of k-space.

This application is a continuation of application Ser. No. 09/899,353,filed Jul. 5, 2001 now U.S. Pat. No. 6,889,072, which is a continuationof application Ser. No. 09/061,101, filed Apr. 16, 1998 now U.S. Pat.No. 6,278,892, which is a continuation of application Ser. No.08/705,818, filed Aug. 30, 1993 now U.S. Pat. No. 5,762,065, which is acontinuation of Ser. No. 08/378,384, filed Jan. 25, 1995 now U.S. Pat.No. 5,553,619, which is a continuation-in-part of application Ser. No.08/071,970, filed Jun. 7, 1993 now U.S. Pat. No. 5,417,213.

BACKGROUND OF THE INVENTION

This invention relates to a method of, and apparatus for use in,magnetic resonance angiography to detect, diagnose, and treat arterialdiseases and injuries. Arterial diseases and injuries are common andoften have severe consequences including death. Imaging arteries servesto detect and characterize arterial disease before these consequencesoccur.

A conventional method of arterial imaging includes inserting a catheterinto the artery of interest (the artery under study) and injectingradiographic contrast, for example, an iodinated contrast, while takingradiographs of the artery. Radiographs are commonly referred to asX-rays. In this technique, the contrast remains in the arteries for afew seconds during which the arteries appear distinct from both theveins and background tissue in the radiographs.

Although a catheter-based contrast arteriography technique generallyprovides high quality arterial images, there is a risk of arterialinjury or damage by the catheter and its insertion. There may bethrombosis, dissection, embolization, perforation or other injury to theartery itself. Furthermore, such a technique may result in a stroke,loss of a limb, infarction or other injury to the tissue supplied by theartery. In addition, hemorrhage at the catheter insertion or perforationsites may require blood transfusions. Moreover, kidney failure and braininjury may result from the toxic effects of the X-ray contrast.

More recent techniques of arterial imaging are based upon detecting themotion of the blood within the arteries and/or veins. These techniquesinvolve employing magnetic resonance imaging (MRI) to image moving blooddistinct from stationary background tissues. (See, e.g., Potchen, etal., eds., “Magnetic Resonance Angiography/Concepts and Applications”,Mosby, St. Louis, 1993; the text of which is incorporated herein byreference). Such techniques do not necessitate catheter insertion intothe artery. These techniques are commonly known as 2D time-of-flight, 3Dtime-of-flight, MOTSA, magnitude contrast, phase contrast, and spin echoblack blood imaging.

With pre-saturation pulses it is possible to primarily image bloodflowing in one direction. Since arteries and veins generally flow inopposite directions, these pre-saturation pulses allow preferentialvisualization of the arteries or the veins. Because these techniquesdepend upon blood motion, the images are degraded in patients who havearterial diseases which decrease or disturb normal blood flow. Suchtypes of arterial diseases that decrease or disturb normal blood flowinclude aneurysms, arterial stenoses, arterial occlusions, low cardiacoutput and others. The resulting lack of normal blood flow isparticularly problematic because it is those patients with disturbedblood flow in whom it is most important to acquire good quality arterialimages.

A related magnetic resonance imaging technique relies upon differencesin the proton relaxation properties between blood and backgroundtissues. (See, e.g., Marchal, et al., in Potchen, et al., eds., supra,pp. 305-322). This technique does not depend upon steady blood in-flow.Instead, this magnetic resonance imaging technique involves directlyimaging the arteries after administering a paramagnetic contrast agent.Here, after administering the contrast agent, it is possible to imagearteries directly based upon the blood relaxation properties. Thistechnique overcomes many of the flow related problems associated withmagnetic resonance imaging techniques which depend upon blood motion.

Several experts have performed magnetic resonance arterial imaging usingintravenous injection of gadolinium chelates (paramagnetic contrastagents). These experts have reported their results and conclusions. Inshort, these results have been disappointing and, as a result, the useof gadolinium for imaging arteries has not been adopted or embraced as aviable arterial imaging technique. The images using this technique aredifficult to interpret because the gadolinium tends to enhance both thearteries and the veins. Since the arteries and veins are closelyintertwined, it is extremely difficult to adequately evaluate thearteries when the veins are visible. Further, the difficulty ininterpretation is exacerbated as a result of contrast leakage into thebackground tissues.

As a result, there exists a need for an improved method of magneticresonance angiography which provides an image of the arteries distinctfrom the veins and which overcomes the limitations of other techniques.Further, there exists a need for an apparatus which facilitatesproviding an image of the arteries distinct from the veins and which maybe implemented in overcoming the limitations of other techniques.

SUMMARY OF THE INVENTION

In one aspect, the present invention is a method of imaging an artery ina patient using magnetic resonance imaging. The method administeringmagnetic resonance contrast agent to the patient prior to and/or duringcollection of image data. The contrast may be administered byintravenous infusion at a rate of infusion sufficient to provide asubstantially elevated or maximum concentration of the contrast agent inthe artery during collection of image data representative of a center ofk-space.

In a preferred embodiment, the administration of the contrast agentincludes temporally correlating a substantially elevated or maximum rateof infusion of the contrast agent with the collection of image datarepresentative of the center of k-space. The rate of infusion andcollection of image data are correlated in accordance with a delay timein a delivery system, a location of the artery and/or a physicalcondition of the patient.

In another preferred embodiment, the method according to this aspect ofthe invention further includes administering the contrast agent at asubstantially elevated or maximum rate of infusion about 10 to about 30seconds before collection of image data representative of the center ofk-space. Where the contrast agent is paramagnetic, a maximum rate ofinfusion may be greater than 0.0015 Liters/Kg-sec² divided by therelaxivity.

Further, in another preferred embodiment, the method may includetemporally correlating a period of a substantially elevated rate ofinfusion with the collection of image data representative of the centerof k-space in accordance with a size of the artery so that theconcentration of the contrast agent in the artery is substantiallygreater than veins adjacent to the artery during collection of imagedata representative of the center of k-space. In this preferredembodiment, the contrast agent may be administered at an infusion rateand for a period which provides a substantially elevated or maximumconcentration of the magnetic resonance contrast agent in the arteryduring more than 50% of the period of collecting image datarepresentative of the center of k-space. The contrast may also beadministered to provide a substantially elevated or maximumconcentration of the magnetic resonance contrast agent in the artery fora period of between about 50% to about 85% of the time of collectingimage data representative of the center of k-space.

In one preferred embodiment, the step of administering the contrastagent to the patient further includes administering a paramagneticcontrast agent having a relaxivity. The paramagnetic contrast agent maybe administered at a rate of infusion sufficient to provide aconcentration of the paramagnetic contrast agent in the artery, duringcollection of image data representative of a center of k-space, ofgreater than 2.9/sec*relaxivity.

In another preferred embodiment, the techniques of this invention isimplemented using a mechanical injector which is spring-loaded,pneumatic powered, or electrically powered. The mechanical injector mayinclude a non-magnetic spring to pressurize the contrast agent forinfusion into the patient. Further, the mechanical injector may beadapted to receive a vessel containing a gadolinium chelate.

In another aspect, the present invention is a method for administering amagnetic resonance contrast agent into a vein of a patient to enhance amagnetic resonance image of an artery of the patient. The methodincludes administering the contrast agent into the vein at an infusionrate and for a period of time sufficient to provide a maximum orsubstantially elevated concentration of contrast in the artery duringcollection of at least a portion of the image data which corresponds toa center of k-space.

In a preferred embodiment of this aspect of the invention, the methodfurther includes administering a paramagnetic contrast agent at amaximum rate of infusion which is greater than 0.0015 Liters/Kg-sec²divided by the relaxivity.

In another preferred embodiment, the method may further includetemporally correlating a maximum rate of infusion of the contrast agentwith the mapping of k-space in accordance with a delay time in adelivery system, a location of the artery or a physical condition of thepatient.

The paramagnetic contrast agent may be administered at a rate ofinfusion sufficient to provide a concentration of the paramagneticcontrast agent in the artery of greater than 2.9/sec*relaxivity duringcollection of image data representative of a center of k-space.

The method of this aspect of the invention may also be implemented usinga mechanical injector which is spring-loaded, pneumatic powered, orelectrically powered. The mechanical injector may be adapted to receivea vessel containing a gadolinium chelate. Further, the mechanicalinjector may include a non-magnetic spring to pressurize the contrastagent for infusion into the patient.

In yet another aspect, the present invention is a magnetic resonancecompatible apparatus for administering a magnetic resonance contrastagent into a vein of a patient to enhance a magnetic resonance image ofan artery of the patient. The apparatus includes a spring-powereddevice, having a non-magnetic spring, for administering the contrastagent into the vein at an infusion rate and for a period of timesufficient to provide a substantially elevated concentration of thecontrast agent in the artery during collection of at least a portion ofthe image data which corresponds to a center of k-space. Thenon-magnetic spring may be manufactured from eljaloy, inconel or othernon-magnetic material.

The magnetic resonance contrast agent, in this aspect of the invention,may be contained in a syringe having an orifice at a distal end and aplunger for engaging the contrast agent. The syringe may be coupled tothe spring-powered device such that the spring-powered device engagesthe plunger of the syringe to administer the contrast agent into thevein at an infusion rate within the range of about 4 ml/minute to about600 ml/minute.

In a preferred embodiment, the apparatus includes a rate adjustmentmechanism coupled to the plunger of the syringe to adjust the infusionrate of the contrast agent. Further, the apparatus may also include afluid flow restrictor coupled to the orifice of the syringe to control,in combination with the non-magnetic spring, the infusion rate of thecontrast agent. The fluid flow restrictor may be a needle, a precisionorifice, or tubing having a narrow calibre.

The apparatus may also include a flow rate indicator to visually oraudibly indicate the infusion rate of the contrast.

In still yet another aspect, the present invention is an apparatus foradministering a magnetic resonance contrast agent into a vein of apatient to enhance a magnetic resonance image of an artery of thepatient. The apparatus includes an infusion mechanism, includinginfusion means for matching the infusion rate with the mapping of atleast a portion of k-space. The infusion means infuses the contrastagent at a rate and duration sufficient to provide a maximum or elevatedconcentration of the contrast agent in the artery during collection ofat least a portion of the image data which corresponds to a center ofk-space.

Finally, in another aspect, the present invention is an apparatus forinjecting a magnetic resonance contrast agent into a patient, includingan injection mechanism to match a substantially elevated or maximumcontrast agent concentration in the artery relative to adjacent veinswith a mapping of k-space by controlling the rate of flow of thecontrast agent such that a substantially elevated rate of flowcorrelates with the collection of image data corresponding to a centerof k-space.

In a preferred embodiment, the injection mechanism may temporallycorrelate the substantially elevated or maximum rate of infusion withthe collection of image data corresponding to the center of k-space.This correlation may be in accordance with a location of the arteryand/or the time delay inherent in the infusing apparatus.

The injection mechanism may provide a substantially elevated or maximumrate of infusion of the contrast agent about 10 to about 40 secondsbefore beginning collecting image data which corresponds to the centerof k-space.

In a preferred embodiment, the injection mechanism temporally correlatesa period of a substantially elevated or maximum rate of infusion of thecontrast agent with the collection of image data corresponding to thecenter of k-space in accordance with a size of the artery. This providesfor a situation where the concentration of the contrast agent in theartery is substantially greater than adjacent veins while collectingimage data which corresponds to the center of k-space. In anotherpreferred embodiment, the injection mechanism includes means forinfusing the contrast agent into the patient at a rate and duration ofinfusion which provides a substantially elevated or maximumconcentration of the magnetic resonance contrast agent in the artery forat least 50% of the time of collecting image data corresponding to thecenter of k-space.

The present invention overcomes the limitations of other techniques byinjecting magnetic resonance contrast agents at a sufficient rate, at aselected time relative to the collection of image data, and for anappropriate duration in such a manner that the contrast level in thearteries is higher than that in surrounding veins and background tissueduring collection of image data. The injection may be intravenously in avein remote from the artery of interest. Intravenous injectioneliminates the risks associated with arterial catheterization. In thepresent invention, the high level of arterial contrast permits directlyimaging the arterial lumen, analogous to conventional arteriography.Moreover, using a magnetic resonance pulse sequence which is not assensitive to motion and by relying on image contrast related todifferences in T1 relaxation rather than the in-flow effect, a reductionin the flow artifacts associated with phase contrast or magnitudecontrast (time-of-flight) magnetic resonance angiography is observed.

In short, the present invention is, in comparison or relative to othertechniques, a method of magnetic resonance angiography which combinesseveral of the advantages of catheter-based contrast arteriography withthe advantages of magnetic resonance imaging while substantiallyeliminating the disadvantages of each.

BRIEF DESCRIPTION OF THE DRAWINGS

In the course of the detailed description of preferred embodiments tofollow, reference will be made to the attached drawings, in which:

FIG. 1 illustrates longitudinal relaxation time (T1) of blood as afunction of injection imaging time and total paramagnetic contrast dosefor a compound with a relaxivity of 4.5/millimolar-second;

FIG. 2 illustrates calculated magnetic resonance signal intensity as afunction of flip angle for 5 different longitudinal relaxation times(T1) assuming a spoiled, 3D volume acquisition with TR equal to 25 msecand TE<<T2*;

FIGS. 3, 4, 5A and 5B, and 6A-C are block diagram representations ofmechanical infusion devices and configurations, according to the presentinvention;

FIG. 7 is a block diagram representation of a manual injectionconfiguration, according to the present invention;

FIGS. 8A-C illustrate typical coronal maximum intensity projection (MIP)collapse images obtained (FIG. 8A) prior to injection of gadopentetatedimeglumine, (FIG. 8B) dynamically during intravenous injection ofgadopentetate dimeglumine, 0.2 millimoles/kilogram over 5 minutes, and(FIG. 8C) immediately following injection of gadopentetate dimeglumine;

FIG. 9 illustrates region of interest analysis averaged for 3 patientswho had pre-infusion, dynamic infusion, immediate post infusion anddelayed 3D FT imaging. This figure shows that there is a short window,during contrast infusion, when the aorta signal intensity (solidsquares) is higher than that of the IVC (open squares) and backgroundtissues, fat (diamonds) and muscle (triangles);

FIG. 10A is an illustrative example of a magnetic resonance image of apatient with an abdominal aortic aneurysm. The magnetic resonanceangiography (“MRA”) depicts the aneurysmal aorta and aneurysmal commoniliac arteries as well as severe stenoses of the right external iliac(curved arrow) and inferior mesenteric (straight arrow) arteries and amild stenosis of the left common iliac artery; and

FIG. 10B illustrates a digital subtraction angiogram of the aneurysmalaorta and aneurysmal common iliac arteries as well as severe stenoses ofthe right external iliac (curved arrow) and inferior mesenteric(straight arrow) arteries and a mild stenosis of the left common iliacartery of FIG. 10A.

DESCRIPTION OF A PREFERRED EMBODIMENTS

Briefly, the present invention is a technique and apparatus forproviding preferential enhancement of an artery of interest relative toadjacent veins and background tissue by adapting the timing of a maximumor substantially elevated rate of infusion to correlate with thecollection of image data representative of the center of k-space. Thetechnique and apparatus temporally correlates the timing of a maximum orsubstantially elevated rate of infusion and the mapping of k-spaceaccording to the location of the artery of interest, the size of theartery of interest, the physical condition of the patient, the timedelay due to the configuration of the contrast agent delivery system,and/or the type of pulse sequence employed by the imaging apparatus.Adapting the timing of a maximum or substantially elevated rate ofinfusion to correlate with the collection of image data corresponding tothe center of k-space provides a period of a maximum or substantiallyelevated contrast concentration in the artery of interest relative toadjacent veins during collection of at least a portion of the image datarepresentative of the center of k-space.

In particular, in one aspect, the present invention is a method ofmagnetic resonance angiography wherein the magnetic resonance imagingdata is collected over a period with simultaneous controlled intravenousinjection of a magnetic resonance contrast agent. The magnetic resonancecontrast agent is preferably injected into a patient, for example, ahuman or other animal, substantially throughout the period of imaging ina controlled manner, i.e., injected at a controlled rate over the periodof imaging. In a preferred embodiment, the magnetic resonance contrastagent is administered as a steady and continuous infusion in a veinwhich is remote from the artery of interest (i.e., the artery understudy).

The method and apparatus of this invention is especially useful inimaging peripheral arteries. A peripheral artery is an artery that isoutside the brain. Since the blood-brain barrier prevents redistributionof the contrast agent from the capillary bed in the brain, thisinvention is more effective in imaging arteries found in a patient'sbody which are below the neck.

Magnetic resonance contrast agents employed in the present invention arewell known in the art, and are disclosed in, for example, U.S. Pat. Nos.5,141,740; 5,078,986; 5,055,288; 5,010,191; 4,826,673; 4,822,594; and4,770,183, which are incorporated herein by reference. Such magneticresonance contrast agents include many different paramagnetic contrastagents, for example, gadolinium compounds. Gadopentetate dimeglumine andgadoteridol are paramagnetic gadolinium chelates that are readilyavailable, and which rapidly redistribute into the extracellular fluidcompartment. Other gadolinium compounds are acceptable, and may have ahigher relaxivity, more rapid redistribution into the extracellularfluid compartment, and greater and faster extraction in the capillarybed. It should be noted that, contrast agents that are extracted ordegrade in or near the capillary bed are preferred for the presentinvention.

In one preferred embodiment, the injected magnetic resonance contrastagent should be sufficiently small to rapidly redistribute into theextracellular fluid compartment in the systemic capillary bed, or thecontrast agent should be actively extracted from the circulation in thecapillary bed distal to the artery of interest, or both. Under thesecircumstances, the artery (or arteries) of interest contains a highconcentration of contrast and the vein (or veins) adjacent to the artery(or arteries) of interest possesses a low contrast concentration.Further, under these circumstances, the relationship of artery-to-venouscontrast concentration is substantially maintained over the period ofcontrast injection.

By matching the duration of the injection with the time required for alongitudinal relaxation time (T1) weighted magnetic resonance image dataset, it is possible to view the arteries distinct from the veins.Further, by injecting the contrast at a sufficient rate, thelongitudinal relaxation time of the arterial blood may be madesufficiently short when compared to that of the background tissues. As aresult, the image of the arteries is distinct from background tissue aswell.

As mentioned above, the magnetic resonance contrast agent isadministered to the patient, for example, a human or other animal, viaintravenous infusion, i.e., injection into a patient at a controlledrate over a period of time. In a preferred embodiment, the period ofinfusion of magnetic resonance contrast agent may be a substantialportion of the time during which image data is being collected for amagnetic resonance image. A substantial portion of the data collectiontime is a majority of the time and should include the period of timeduring which the center of k-space is acquired. A substantial portion ofthe data collection may be at least 75% of the collection period, andpreferably greater than 85% of the collection period.

In another preferred embodiment, a maximum or elevated rate of infusionis correlated with collecting of image data representing the center ofk-space. That is, a maximum or elevated rate of injection of contrastoccurs while mapping the center of k-space. The center of k-space refersto the low spatial frequency MR image data. In a preferred embodiment,the timing of the infusion of the magnetic resonance contrast agent(e.g., gadolinium), however, is compensated to account for the timewhich may be necessary for the contrast agent to circulate from the siteof injection, through the heart and lungs, and into the artery ofinterest. Under this circumstance, in order to more accurately correlatea maximum or elevated rate of infusion of the contrast agent withcollection of image data representative of the center of k-space, it maybe necessary for the period of a maximum or substantially elevated rateof infusion of contrast to be forwardly shifted in time relative to theacquisition or collection of image data representing the center ofk-space.

Correlating the maximum or substantially elevated rate of infusion withthe mapping of k-space accounts for the time delay due to the contrastagent delivery system (e.g., the length of catheter which delivers thecontrast agent) and/or the time-delay due to the time required for thegadolinium to circulate from the site of injection, through the body,and into the artery of interest. Further, correlating a maximum orelevated rate of infusion with the mapping of the center of k-spaceprovides for a period of maximum or elevated arterial contrast in theartery of interest to occur during collection of image datacorresponding to the center of k-space (which in most pulse sequences iscollected during the middle of a scan).

Typically, there is a delay of about 10-40 seconds from the time ofadministering the contrast agent at a maximum or substantially elevatedrate to the realization of a maximum or elevated arterial contrast inthe artery of interest relative to adjacent veins. As a result, theamount of time necessary to align the collection of data representingthe center of k-space with a period of maximum or elevated arterialcontrast is about 10 to 40 seconds after initiating maximum orsubstantially elevated rate of infusion. That is, the maximum orsubstantially elevated rate of infusion should occur about 10 to 40seconds prior to acquiring image data representative of the center ofcenter of k-space to “compensate” for the contrast delivery system andthe circulation time of the contrast agent. In this regard, the maximumrate of infusion of the contrast agent is correlated with the collectionof image data which corresponds to the center of k-space in that aperiod of maximum or elevated arterial contrast occurs during themapping of the center of k-space.

In some instances, the pulse sequence of the imaging apparatus may bedesigned such that data representing the center of k-space is collectedat the beginning of a scan. Under this circumstance, the above describedtechnique may be implemented by injecting contrast agent prior to theimage scanning process (collection of image data) so that the injectionof the contrast agent is properly correlated to the acquisition of datacorresponding to the center of k-space and a period of maximum orelevated arterial contrast coincides with that data acquisition.

In one preferred embodiment, the timing of the infusion of the contrastagent may be further adjusted according to the physical condition of thepatient. That is, the timing of the administration of the contrast agentto, for example, correlate a maximum or elevated rate of infusion withthe mapping of k-space, may be adjusted according to a patient'sphysical condition which may affect the amount of time for contrast tocirculate from the site of infusion (typically an arm vein) to theartery of interest. Although this time interval will typically be about10-40 seconds, patients with cardiac disease or under sedation may havea slower flow, which may suggest a time interval of about 30 seconds orgreater.

In contrast, young healthy patients, and especially patients who haverecently exercised, will have a faster flow, which may suggest a timeinterval of less than 20 seconds. Faster flow is also seen in patientswith arterio-venous fistulas. The circulation time will also bedecreased in patients who have central lines that allow injection ofcontrast close to or directly into the heart.

In another preferred embodiment, the timing of a maximum orsubstantially elevated infusion rate may be further selected orcontrolled, based on the location of the artery of interest relative tothe injection site and/or the patient's heart, to provide a period ofmaximum or elevated arterial contrast concentration in the artery ofinterest relative to adjacent veins during collection of image datawhich corresponds to the center of k-space. In this regard, the amountof time between a maximum or elevated rate of injection and a maximum orelevated arterial contrast is realized in the artery of interest may belonger if the artery of interest is far from the heart, for example, inthe foot, or if the site of infusion is a peripheral vein such as in thehand. Thus, in this preferred embodiment, the correlation of the maximumrate of injection with the collection of image data representative ofthe center of k-space includes adapting the time between the maximumrate of injection and the mapping of the center of k-space to reflectthe relative location of the artery of interest.

In another preferred embodiment, the correlation between a maximum orelevated rate of injection and the collection of image datarepresentative of the center of k-space may be adjusted or controlled inaccordance with the size of the artery of interest. This is because thevarying image contrast during image acquisition creates artifacts. Ifthe arteries have a high concentration of contrast for only a shortperiod of time when the center of k-space is acquired, then theartifacts will be larger, making it possible to evaluate only thelargest of arteries. In order to see small arteries free of artifacts,it is necessary to have a high concentration of gadolinium in the arteryfor a substantial fraction of the image acquisition time, including theperiod corresponding to acquisition of the center of k-space. In thisregard, the duration for which the magnetic resonance contrast agent isadministered at a maximum or elevated rate during collection of imagedata corresponding to the center of k-space may be adapted according tothe size of the artery of interest. This provides for a period ofoverlap between a maximum or elevated concentration of contrast in theartery of interest and mapping of the center of k-space (i.e., overlapcorrelation factor). The overlap correlation factor may be defined asthe amount of time during which an elevated or maximum arterial contrastexists in the artery of interest relative to the collection of imagedata representing the center of k-space. The overlap correlation factormay also be defined as the duration of overlap between the collection ofimage data representative of the center of k-space and a maximum orelevated rate of injection of the contrast agent. Where the artery ofinterest is relatively large (e.g., the aorta), an elevated or maximuminjection rate of the contrast agent may overlap with the collection ofimage data representative of the center of k-space for a shorter periodof time. In contrast, where the artery is relatively small (e.g., arenal artery), the contrast agent may be administered at an elevated ormaximum rate for a longer period of time during the mapping of thecenter of k-space.

Further, when imaging larger arteries, in a preferred embodiment, anelevated or maximum concentration of contrast agent in the artery ofinterest is provided for at least 20% of the time during which imagedata corresponding to the center of k-space is collected; andpreferably, an elevated or maximum concentration of contrast in theartery of interest is maintained for between 20% to 50% of the mappingof the center of k-space. This, translates into correlating a period ofsubstantially elevated or maximum rate of injection with the period ofcollection of image data corresponding to the center of k-space so thatduring at least 20% of the time of mapping k-space, a substantiallyelevated or maximum concentration of contrast agent is maintained in theartery of interest relative to adjacent veins; and preferably about 50%.

When imaging smaller arteries, in a preferred embodiment, an elevated ormaximum concentration of contrast agent in the artery of interest isprovided for greater than 50% of the time during which image datacorresponding to the center of k-space is collected; and in a morepreferred embodiment, an elevated or maximum concentration of contrastin the artery of interest is maintained for greater 75% of the mappingof the center of k-space. As a result, where the artery of interest isrelatively small, the administration of the contrast agent may include amaximum or elevated rate of injection of the contrast agent of greaterthan 50% of the time of mapping of the center of k-space; and preferablybetween 50% to 85%, and most preferably greater than 75%. Under thiscircumstance, fewer artifacts are observed in the smaller vessels orarteries when the contrast is administered at a maximum or elevated rateover a longer period of the k-space mapping.

It is noted that, in the aforementioned embodiment, the period of amaximum or substantially elevated rate of injection may also becompensated according to other factors including, the time delay due tothe delivery system, the location of the artery, and the physicalcondition of the patient.

During the acquisition of image data corresponding to the center ofk-space, it may be important to avoid excessively rapid changes inarterial contrast concentration. Rapidly changing blood signal duringacquisition of the center of k-space may create image reconstructionartifacts. These artifacts may be minimized when the arterial signalintensity is uniform. Further, these artifacts may be minimized byslowly changing the arterial concentration during acquisition of imagedata and especially during acquisition of the center of k-space.

In those instances where the invention is implemented using paramagneticcontrast agents, infusion is at a rate that will provide a concentrationof the agent in the arteries, such that the arteries will appear atleast 50% brighter than any background structures, including veins, inthe final image. In a preferred embodiment, the concentration ofcontrast agent will cause the longitudinal relaxation time (T1) of theprotons in the arteries to be shorter than protons in any of thebackground material. Where the contrast agent causes the arteries toappear black in the final image (e.g., where the contrast agent shortensT2*, for example, Fe powder), the contrast agent should be infused at arate and amount to insure that the effective transverse relaxation time(T2*) in the arteries is shorter than in any of the background material.

Any apparatus suitable for magnetic resonance imaging (MRI) of a portionof an animal body, for example, a human, may be used for acquisition ofimage data in the method of this invention. In particular, apparatus andimaging methods for magnetic resonance angiography are known in the art(see, e.g., U.S. Pat. Nos. 4,718,424; 5,034,694; and 5,167,232,incorporated herein by reference), and these may be used with the methodof MRA with dynamic intravenous injection of magnetic resonance contrastagents taught herein, subject only to the constraints taught below.

The parameters of the imaging method of the present invention arediscussed immediately below with respect to gadolinium chelates. Itshould be noted that other magnetic resonance contrast agents may beemployed in practicing the present invention including paramagneticcontrast agents, such as those described by Marchal, et al., in Potchen,et al., eds., supra, pp. 305-322, the text of which is incorporatedherein by reference.

Injection Parameters

Gadolinium chelates are paramagnetic agents which shorten thelongitudinal relaxation time, T1, of blood according to EQUATION 1:

$\begin{matrix}{\frac{1}{T1} = {\frac{1}{1200} + {{Relaxivity} \times \lbrack{Gd}\rbrack}}} & (1)\end{matrix}$

where:

-   -   (1) the longitudinal relaxation time (T1) of blood without        gadolinium is 1200 milliseconds; and    -   (2) [Gd] is the blood concentration of a gadolinium chelate.

With reference to EQUATION 1, to achieve an arterial blood (T1) that isshort compared to adjacent fat (T1=270), it is necessary tosubstantially elevate the arterial blood concentration of the contrastagent in the artery of interest to be greater than ( 1/270 milliseconds-1/1200 milliseconds)/relaxivity of the contrast agent (or2.9/seconds*relaxivity). Thus, the artery of interest includes asubstantially elevated concentration of the contrast agent when thatconcentration is greater than 2.9 seconds⁻¹ relaxivity⁻¹ of the contrastagent.

A substantially elevated rate of infusion provides a substantiallyelevated concentration of the contrast agent in the artery of interest.That is, a substantially elevated rate of infusion provides an arterialblood concentration of the contrast in the artery of interest which isgreater than 2.9 seconds⁻¹ relaxivity⁻¹ of the contrast.

As reflected in EQUATION 2, below, the arterial blood [Gd] may beexpressed in terms of the intravenous injection rate and the cardiacoutput during dynamic imaging at times short as compared to therecirculation time.

$\begin{matrix}{\lbrack{Gd}\rbrack_{arterial} = {\frac{{Injection}\mspace{14mu}{Rate}}{{Cardiac}\mspace{14mu}{Output}} + \lbrack{Gd}\rbrack_{venous}}} & (2)\end{matrix}$

As long as the gadolinium chelate is sufficiently small, the gadoliniumchelate will rapidly redistribute into the extracellular compartment asit passes through the capillary bed and the venous concentration will below or negligible compared to the arterial concentration. Therelationship between the longitudinal relaxation time of arterial bloodand the injection rate may then be determined by combining EQUATION 1and EQUATION 2, as stated below in EQUATION 3:

$\begin{matrix}{{{Injection}\mspace{14mu}{Rate}} = {\frac{\left\lbrack {\frac{1}{T\; 1} - \frac{1}{1200}} \right\rbrack}{Relaxivity} \times {Cardiac}\mspace{14mu}{Output}}} & (3)\end{matrix}$

To achieve contrast between arterial blood and background tissue, thelongitudinal relaxation time of the arterial blood should be reduced toless than that of the background tissues. Of all types of backgroundtissues, fat (T1=270 msec) typically has the shortest longitudinalrelaxation time. Assuming a typical minimum resting cardiac output of0.0005 Liters/Kg-sec and requiring the longitudinal relaxation time tobe less than 270 milliseconds simplifies EQUATION 3 to EQUATION 4 asshown below:

$\begin{matrix}{{{Injection}\mspace{14mu}{Rate}} > \frac{0.0015\mspace{14mu} L\text{/}{Kg}\text{-}\sec^{2}}{Relaxivity}} & (4)\end{matrix}$

By way of example, gadopentetate dimeglumine, gadodiamide, andgadoteridol are three paramagnetic gadolinium chelates that are readilyavailable and rapidly redistribute into the extracellular fluidcompartment. The relaxivities of gadopentetate dimeglumine andgadoteridol are 0.0045/molar-second. Based upon the aforementioned andusing EQUATION 4, the minimum injection rate is greater than 0.033millimole/Kg-minute.

With continued reference to EQUATION 4, a rate of infusion which isgreater than 0.0015 Liters/Kg-sec² divided by the relaxivity may providea maximum concentration of the contrast agent in the artery of interest.That is, infusing the contrast into the patient at a rate of greaterthan 0.0015 Liters/Kg-sec² divided by the relaxivity may yield a maximumarterial blood concentration of the paramagnetic contrast agent.

The total dose of gadolinium chelate required may be determined bymultiplying the injection rate by the imaging time. For a relaxivity of4.5/millimolar-second, and an imaging time of 5 minutes (300 seconds),the dose should substantially exceed 0.1 millimole/kilogram.

The dose of the gadolinium chelate may be within the range of 0.05millimoles/kilogram body weight to 1 millimoles/kilogram body weightdepending upon the time required to obtain the image. It should be notedthat the dose of the contrast should not be too high such that there maybe undesirable toxicity or T2 effects. In a preferred embodiment, thedose of the gadolinium chelate is within the range of 0.2millimoles/kilogram body weight to 0.4 millimoles/kilogram body weight.In a more preferred embodiment, the dose of the gadolinium chelate isabout 0.3 millimoles/kilogram body weight.

In those instances where the contrast injection times are longer thanthe recirculation time, the longitudinal relaxation time of arterialblood tends to be even shorter since a fraction of the gadoliniumchelate will recirculate. It should be noted that a T1 of 270 ms(corresponding to the brightest background tissue fat) is equivalent toa gadopentetate dimeglumine concentration of 0.6 millimole/liter.

FIG. 1 illustrates the longitudinal relaxation time (T1) of blood as afunction of infusion time and the total paramagnetic contrast dose for aparamagnetic contrast compound having a relaxivity of4.5/millimolar-second. An examination of FIG. 1 reveals that theshortest T1 occurs with the shortest infusion time and the largestgadolinium dose. For typical imaging times of 3 to 5 minutes, FIG. 1further reveals that the dose should be of the order of 0.2millimoles/kilogram or larger in order to achieve a longitudinalrelaxation time of blood significantly shorter than that of thebrightest background tissue fat (T1=270) for the entire duration ofimaging.

Imaging Parameters

Any suitable T1 weighted magnetic resonance imaging sequence may be usedduring injection of the paramagnetic contrast. Suitable imagingsequences will be readily apparent to the skilled practitioner and aredescribed in Potchen, et al., eds., supra. The following criteria forselection of preferred imaging parameters are based on experience inover 100 patients on a 1.5 Tesla General Electric signa magnet withversion 4.7 software. A three-dimensional Fourier Transform (volume)acquisition (3D FT) is preferred in the abdomen because of itsintrinsically high spatial resolution and high signal-to-noise ratio,even with a large, body coil. The gradient echo (gradient recalled)pulse sequences are preferred since they allow a short TR (repetitiontime) which allows a shorter imaging acquisition time. Short imagingtimes have the advantage of allowing the same total gadolinium dose tobe injected at a faster rate.

Spoiled Versus Non-Spoiled Gradient Echo Imaging

It should be noted that one might expect steady state gradient echoimaging (GRASS) to be preferable to the spoiled gradient echo imagingbecause the long T2 (transverse relaxation time) of blood increases thesteady state blood signal. However, this effect enhances veins more thanarteries, because the fast, pulsatile flow of arterial blood spoils itssteady state component. In theory, this may have the paradoxical effectof reduced arterial contrast. In practice, there may only be a smalldifference between the spoiled and unspoiled techniques. In patientswith slow arterial flow (which is not self-spoiling), steady stategradient echo may be preferred. A spoiled gradient echo pulse sequence(SPGR) was chosen for most of the studies described herein to simplifythe theory and analysis to reduce the potential for differential steadystate magnetization between arterial blood, slower venous blood andbackground tissue.

Echo Time

Because the brightest background tissue is fat, it is preferable to usea TE (echo time) where fat and water are out of phase, thereby achievingan incremental improvement in vessel-to-background contrast. At 1.5Tesla, this occurs about every 4.6 msec beginning at 2.3 msec whichcorresponds to a TE of 2.3, 6.9, 11.5, . . . msec. The shortest of thesepossible TE values (6.9 msec in the studies described herein) ispreferred. Shorter TE's tend to minimize the effects of motion relatedphase dispersion.

Repetition Time

In a preferred embodiment, TR should be as short as is possible. A TR of24-25 msec was the shortest possible on the equipment used for thestudies described herein. As the TR is shortened, the flip angle must beadjusted to maintain the optimal T1 weighing.

Flip Angle

With a gadolinium chelate dose of 0.2 millimoles/kilogram and a 3-5minute injection time and imaging time, the longitudinal relaxation timeof the arterial blood is predicted to be in the order of 150 to 200milliseconds. It will, however, be shorter as a result of therecirculation time being less than 3-5 minutes. The relative signalintensity, SI, in a 3D FT spoiled gradient echo acquisition as afunction of blood T1, TR, T2, T2*, flip angle σ, and proton density N(H)may be expressed as stated in EQUATION 5, below, and calculatedaccordingly.

$\begin{matrix}{{SI} = {{N(H)}\frac{1 - {\exp\left( {- \frac{TR}{T\; 1}} \right)}}{1 - {{\cos(\alpha)}{\exp\left( {- \frac{TR}{T\; 1}} \right)}}}{\sin(\alpha)}{\exp\left( {- \frac{TE}{T\; 2^{*}}} \right)}}} & (5)\end{matrix}$

FIG. 2 graphically illustrates relative signal intensity for T1 equal to50, 100, 150, 270 (fat), and 1200 (blood) under the followingconditions: (1) TR=25 milliseconds, and assuming TE is small compared toT2* (the observed transverse relaxation time). FIG. 2 reveals that aflip angle of about 40 degrees is optimal for maximizingblood-to-background tissue (fat) contrast when the longitudinalrelaxation time (T1) of blood is of the order of 200 milliseconds. Forlarger gadolinium doses with faster injection rates, a larger flip anglemay be more appropriate.

Volume Orientation

In order to minimize the image acquisition time, the imaging volumeshould be made as thin as possible while containing the arteries ofinterest. In this regard, it may be useful to orient the image volumefor maximum in-plane coverage of the vessels of interest as opposed tothe perpendicular orientation required for optimal time-of-flightmagnetic resonance angiography. Optimizing the orientation andminimizing the thickness of the imaging volume is facilitated by firstacquiring a conventional black-blood or time-of-flight MRI to use as aguide for precise localization. Phase and frequency encoding axes shouldbe oriented such that cardiac and respiratory motion artifacts do notsuperimpose on the vessels of interest. Generally, for imaging theaorta-iliac system, the imaging volume should be oriented coronally, andthe phase encoding axis should be set right-to-left. For imaging thethoracic aorta, a sagittal orientation is preferred and for imaging thesubclavian arteries, an axial orientation is preferred.

Partitions

The number of partitions (slices) is determined by the thickness of theimage volume divided by the partition thickness. The partition thicknessis the image resolution along the axis perpendicular to the plane of thepartitions. It may be useful to employ thin partitions in order to havehigh image resolution. The image acquisition time, however, linearlyincreases with the number of partitions. As a result, keeping the imageacquisition time short requires minimizing the number of partitions.

It should be noted that there may be a loss of signal-to-noise as thevoxel size is decreased by using higher resolution pixels. Generally,0.5 to 2 millimeter resolution with 28 to 60 partitions is adequate forthe aorta and major branch vessels. The skilled practitioner willbalance the need to increase resolution by decreasing voxel size withthe need to avoid excessive periods of time to acquire image data.

Field-of-View

The field-of-view must be made large enough to avoid excessivewrap-around artifact. Wrap around artifacts occur when there arestructures outside the field of view along the phase encoding axis.These structures are mapped by the phase encoding process to superimposeon structures within the field of view.

In addition, because of the limited number of pixels along the frequencyencoding axis and time penalty for each additional pixel along the phaseencoding axis, it is also desirable to make the field-of-view as smallas possible in order to maximize image resolution with the minimum imageacquisition time. Generally, for imaging the abdominal or thoracicaorta, a field-of-view of about 36 centimeters is appropriate for mostpatients. It may be increased for larger patients and reduced forsmaller patients. Smaller field-of-views may be used for other parts ofthe body.

Use of a no-phase wrap algorithm is a less preferred embodiment. Underthe circumstance of this invention, this has a disadvantage of generallyrequiring more imaging time and, as a result, a larger gadolinium dose.

Coils

It is preferable to use the smallest possible coil in order to minimizenoise. There is also an advantage to coils that encircle the body partof interest such that the signal will be homogeneous throughout theentire field-of-view.

Patient Positioning

The patient should be positioned such that the body part being imagedremains stationary during the acquisition of image.

Cardiac and Respiratory Motion Compensation

The phase artifact related to respiratory and cardiac motion may beminimized by combining the T1 weighted imaging sequence with respiratoryor electrocardiographic gating. Gating has the disadvantage ofincreasing the scan time—particularly in patients with irregularrhythms. Compensation techniques in which the acquisition of the imagedata in k-space is matched to the respiratory and or cardiac cycle mayeliminate some phase artifact without significantly increasing the scantime.

In imaging regions of the body that move substantially with respiration(e.g., the renal arteries) it may be useful to acquire data while thepatient is holding his breath. This may require shortening the durationof the image acquisition time to under one minute. If the patient cannothold his breath for the entire period of image acquisition, than it maybe useful to hold the breath during acquisition of image datacorresponding to the center of k-space and breathing only duringacquisition of data corresponding to the periphery of the center ofk-space.

Pre-Scanning

The pre-scanning process is used to tune to the optimum frequency and tooptimize the receiver gain. In the pre-scanning process, it is necessaryto compensate for the changes in the patient's magnetic resonance signalthat will occur during the contrast injection. In those instances whenthe paramagnetic contrast agent is a gadolinium chelate, it ispreferable to tune to the water peak. About a 20% to 50% margin shouldbe incorporated into the receiver gain setting to allow for increasedsignal during contrast administration.

Premedication

Premedicating patients with an analgesic or sedative such as diazepammay be useful for at least two reasons. Firstly, it may help the patientto tolerate the claustrophobic sensation of being within the magnetthereby reducing voluntary motion artifacts. Secondly, and moreimportantly, its relaxation and cardiac depressant effects tend toreduce the cardiac output. A lower cardiac output results in a higherarterial contrast concentration which thereby improves the imagequality. This result is opposite from conventional magnetic resonanceangiography which is degraded when the cardiac output decreases. Byreducing the cardiac and respiratory rates, analgesics and sedatives mayminimize the fraction of the image acquisition that is adverselyaffected by cardiac and respiratory motion artifacts.

Magnetic Resonance Contrast Agents

As mentioned above, many different magnetic resonance contrast agentsmay be employed when implementing the present invention; for example,numerous paramagnetic contrast agents are suitable. As mentioned above,gadolinium compounds, for example, paramagnetic gadolinium chelates,such as gadopentetate dimeglumine and gadoteridol, are readily availableand rapidly redistribute into the extracellular fluid compartment. Othergadolinium compounds are acceptable. In general, preferred contrastagents have a high relaxivity, rapid redistribution into theextracellular fluid compartment, and are readily extracted from thecapillary bed. It should be noted that, contrast agents that areextracted or degrade in the capillary bed are preferred in the presentinvention.

In particular, gadolinium chelates are commercially available from suchcompanies as Bristol Meyers (under the name “Prohance”), Berlex (underthe name “Magnevist”), and Sterling Pharmaceutical (under the name“OmniScan”). It should be noted that the gadolinium chelate which iscommercially available from Sterling Pharmaceutical, now Nycomed,appears to facilitate greater contrast enhancement between the arteryand the surrounding veins and tissue.

Injection

In a preferred embodiment, the type or form of injection of theparamagnetic contrast is intravenous. The injection of the paramagneticcontrast is performed intravenously in order to eliminate or reduce thecomplications associated with the catheterization required for arterialinjections.

The specific site of injection is important for several reasons. Thesite of injection should be remote from the “region of interest”; thatis, the region that is to be scanned. For example, when imaging theabdominal aorta, intravenous injection of the paramagnetic contrast intoan arm vein is preferred. Use of a leg vein should be avoided. Further,there may be some benefit in avoiding the antecubital fossa because thepatient may bend the elbow during a long (3-5 minute) period ofinjection which may result in extravasation of the contrast into thesubcutaneous tissues. As a result, under this condition, a forearm orupper arm vein may be preferable.

In those instances where an artery in the arm is to be imaged, the siteof the injection may be a leg vein or a vein in the opposite arm. Here,the site of injection is remote from the “region of interest”, i.e., theartery in the arm.

Moreover, it is important to adapt the timing of a maximum or elevatedrate of infusion of the contrast agent to correlate with the collectionof image data which corresponds to the center of k-space. As will bediscussed in more detail below, correlating the infusion rate with themapping of k-space insures that the image data representative of thecenter of k-space is collected over some period during which a maximumor elevated concentration of contrast agent is maintained in the arteryof interest relative to adjacent veins. There are several manners ofadapting the timing of a maximum or substantially elevated rate ofinfusion to correlate a maximum or substantially elevated concentrationof contrast agent with the mapping of k-space, including adjusting thetiming to account for the time delay in the delivery or infusionapparatus, the size and location of the artery of interest, the type ofpulse sequence employed by the imaging apparatus, and the condition ofthe patient.

In a preferred embodiment, as illustrated in FIGS. 3 and 4, a mechanicalinfusion or injection device 12 is an automated type of injector havingreliable and consistent operating conditions. The infusion device 12 isemployed to inject the magnetic resonance contrast agent into the veinof the patient at an infusion rate sufficient to provide contrastenhancement of an image of an artery relative to veins in the field ofview of the magnetic resonance image and substantially throughout theperiod of acquisition of image data. The infusion device 12 couples tothe patient using conventional techniques, for example, appropriatelyselected tubing 14 which permits fluid flow between the mechanicalinfusion device 12 and the patient. Such tubing may be, for example, anangiocatheter.

A mechanical injector is preferred because of the greater reliabilityand consistency when compared to injecting by hand. Since the magneticfield interferes with normal functioning of electronic devices, apneumatic powered, spring loaded or other non-electric pump may besuitable. It should be noted, however, that an electrical pump may beused if its operation is unaffected by the operation of the magneticresonance imaging-system, e.g., if the pump is adequately shielded or ifit is located sufficiently far from the magnet.

In one preferred embodiment, the mechanical infusion device 12 iscoupled to the magnetic resonance imaging system 16 to facilitate properor desired timing between the injection of the magnetic resonancecontrast agent and the acquisition of the image data, in addition toproviding proper or desired rates of infusion of the contrast agent.

In another preferred embodiment, proper or desired timing and rates ofinfusion of the contrast agent are controlled through a controlmechanism at the mechanical infusion device 12. That is, the mechanismthat controls the infusion timing and rates of infusion is implementedwithin the mechanical infusion device 12. In this circumstance, themechanical infusion device 12 is a “self-contained” unit. For example,the infusion rate may be controlled with an adjustable fluid flowresistor.

As mentioned above, the infusion device 12 injects the magneticresonance contrast in a controlled manner. The contrast may be containedin a vessel. As illustrated in FIGS. 3 and 4, the mechanical infusiondevice 12 is coupled to a vessel 18 which contains the magneticresonance contrast agent. In one embodiment, the vessel 18 may contain asufficient quantity of contrast agent for one application of theinvention, e.g., a single use vessel. In an alternative embodiment, thevessel 18 may contain a quantity which allows several applications ofthe invention, e.g., a reservoir type of vessel. As is illustrated inFIG. 3, the mechanical infusion device 12 may be adapted to receive thevessel 18 somewhat like a fountain pen receiving an ink cartridge. In analternative embodiment, as illustrated in FIG. 4, the infusion device 12may be coupled to the vessel 18 using conventional methods.

FIGS. 5A and 5B illustrate a mechanical infusion device 12 in moredetail. The mechanical infusion device 12 of FIGS. 5A and 5B includeseveral of the components described and illustrated in U.S. Pat. Nos.4,202,333; 4,298,000; 4,430,079; and 4,597,754. The descriptions ofthese patents, including several of the components of the mechanicalinfusion device 12 described therein, are incorporated herein byreference. Moreover, such infusion devices are commercially availablefrom 3M Corporation and their product specification sheets are alsoincorporated by reference.

In those instances where the mechanical infusion device 12 is employedwithin the environment of the magnetic field, the infusion device 12should be fitted or manufactured with magnetic resonance compatiblematerial. For example, the infusion devices which are commerciallyavailable from 3M Corp., should be fitted with a magnetic resonancecompatible spring. This requires manufacturing the spring fromnon-magnetic materials, for example, plastic or certain metal alloyssuch as eljaloy or inconel.

To implement the techniques of the present invention and thereby obtaina constant or variable rate of infusion of the magnetic resonancecontrast agent, the device 12 of FIGS. 5A and 5B may include a springwhich has a constant width and thickness in order to exert a constantforce; or, alternatively, the spring may have a variable width and/orvariable thickness to provide a variable spring force. Under thiscircumstance, the infusion rate may be controlled to be either constantor variable by design of the spring and, in effect, pre-programmed byselection of the spring's design parameters.

In one embodiment, the infusion device 12 infuses the magnetic resonancecontrast agent at a variable infusion rate having a maximum or elevatedrate of infusion which temporally correlates with the acquisition ofimage data which is representative of the center of k-space. Under thiscircumstance, data representative of the center of k-space is acquiredduring the period of a maximum or substantially elevated arterialgadolinium concentration in the artery of interest.

As mentioned above, in one preferred embodiment, the timing of a maximumor substantially elevated rate of injection may be correlated to themapping of the center of k-space in accordance with the particulars ofthe delivery systems (e.g., physical length of the catheter/tubing), thelocation of the artery of interest, the size of the artery of interest,and/or the physical condition of the patient. Such a correlationtechnique allows image data corresponding to the center of k-space to becollected during a period of maximum or substantially elevated contrastconcentration in the artery of interest.

It should be noted that the center of k-space may be characterized as10% to 75% of the total k-space data which corresponds to the lowestspatial frequency information.

It should be further noted that a substantially elevated concentrationof the contrast agent in the arterial blood may be described as aconcentration which is greater than 2.9 seconds⁻¹-relaxivity⁻¹. Asmentioned above, a substantially elevated rate of infusion provides asubstantially elevated concentration of the contrast agent in the arteryof interest. In this regard, a substantially elevated rate of infusionprovides a concentration of the contrast in the artery of interest whichis greater than 2.9/seconds-relaxivity (of the contrast).

Further, as mentioned above, a rate of infusion of the contrast agentwhich is greater than 0.0015 Liters/Kg-sec² divided by the relaxivitymay provide a maximum arterial blood concentration of the paramagneticcontrast agent in the artery of interest.

In one preferred embodiment, the infusion device 12 may be designed toaccommodate a 50 cc syringe having a fluid capacity of 60 cc andcontaining one dose of the contrast agent. The infusion device 12 mayalso be designed to permit an external (manual) force on the syringe tomodify or customize the rate of infusion of the contrast agent. Thisexternal force is separate from the force of the spring of the infusiondevice 12.

Further, the infusion device 12 may include a flow rate indicator 50(FIG. 5B) to provide an indication of flow rate of the contrast agent tothe patient. Under this circumstance, the operator may visually oraudibly observe, in a rather simple manner, the rate of flow of thecontrast agent. This will allow the operator to exert an external forcemore accurately (both in the amount of force applied and in a timingsense) thereby facilitating a modification of the predeterminedinjection rate. Further, in an automated-type of infusion device, theflow rate indicator 50 permits the operator to visually or audiblymonitor a “pre-programmed” infusion rate or sequence.

Briefly, reference to FIG. 5A, the mechanical infusion device 12 furtherincludes syringe 24, a syringe clamp 26, a syringe restraint or stop 28,a block and spring housing 30 a, roller bearings 30 b, a reflux valve 32and a catheter 34 having tubing 34 a and a needle 34 b (butterfly type).The syringe 24 contains the contrast agent to be administered to thepatient during magnetic resonance imaging. A plunger 24 a of the syringe24 is engaged by a spring 40 which is housed in the block and springhousing 30 a. In operation, the spring 40 engages the plunger 24 a topressurize the syringe 24. The syringe is maintained in a stationaryposition within the mechanical infusion device 12, and in particular, inhousing base 12 a, via the syringe clamp 26 and the syringe restraint28.

In one preferred embodiment, the mechanical infusion device 12 iscoupled to a saline drip apparatus 42 (saline drip 42 a, tubing 42 b androller clamp 42 c). The saline drip apparatus 42 is applied to an inputof a y-port connector 44. The syringe 24 is applied to the other inputof the y-port connector 44. This conventional configuration facilitatesa saline flush following the administration of the contrast agent withinthe syringe 24. In those instances where the tubing leading from thesaline drip apparatus 42 to the y-port connector 44 has a one-way valveto prevent reflux of contrast, it is acceptable to leave the saline drip“on” during infusion. Under this circumstance, as soon as the infusionof the contrast agent is complete, the drip infusion will automaticallyresume to “flush” gadolinium within the intravenous tubing and deliverthe contrast agent which remains in the tubing to the patient.

The rate of injection of the contrast agent from the syringe 24 isdetermined or controlled, in large part, by the size or gauge of theneedle 34 b, which functions as a fluid flow restrictor according toPoiseulle's Law. The rate of injection is also controlled by the amountof force that the spring 40 (the restoring force of the spring 40)applies to the plunger 24 a of syringe 24, the syringe cross-sectionalarea, the gadolinium viscosity as follows:

${{Infusion}\mspace{14mu}{Rate}} = \frac{\Pi\; r^{4}F}{8L\;\mu\; A}$where:

-   -   r=radius of flow restricting needle lumen;    -   F=spring force;    -   L=length of flow restricting needle;    -   μ=viscosity of the fluid; and    -   A=cross-sectional area of the syringe.

Examining the infusion rate equation immediately above reveals that avariation of the syringe size (A), needle length (L), and/or fluidviscosity (μ) impacts the rate of infusion of the contrast agent. Theviscosity of the fluid, however, may be dependent on the temperature ofthe contrast agent (gadolinium chelate). Thus, in those instances wherethe temperature of the contrast agent alters the viscosity of thecontrast, the rate of infusion is also dependent on this “variable.”

It should be noted, however, that the influence of viscosity on the flowrate may be substantially reduced by employing a fluid flow restrictorwhich minimizes the effects of viscosity on the rate of fluid flow.

In a preferred embodiment, the characteristics of the spring 40 (e.g.,spring force) may be selected or designed such that the spring 40applies a constant force upon plunger 24 a throughout the period ofcontrast infusion. In another preferred embodiment, the characteristicsof the spring 40 may be selected or designed such that the spring 40applies a variable force on the plunger 24 a. That variable force maycorrelate with the imaging process so that a maximum or substantiallyelevated injection rate provides a maximum or substantially elevatedconcentration of contrast in the artery of interest during thecollection of image data which corresponds to the center of k-space.

The rate of injection, however, may be increased or decreased using amanual, spring loaded, or pneumatic injection rate adjustment mechanismwhich may be connected to various components of the device 12,including, the spring 40, the block and spring housing 30 a, the rollerbearings 30 b, the plunger 24 a, the tubing 34 a, and/or the fluid flowrestrictor 34 b. FIG. 5B illustrates a manual injection rate mechanism50 for allowing the operator to readily alter the rate of injection andthereby modify the rate of injection of the contrast agent toaccommodate or implement a desired timing of an elevated or maximum rateof flow of the contrast agent.

The spring force should be sufficient such that the flow restrictor,required to give the desired flow rate, has a flow resistance that ismuch greater than any flow resistance in the intravenous line. Thespring force should not be so high that a person of ordinary strengthcan not reduce or increase this force when a manual spring adjustmentmechanism 50 is designed as the means for adjusting the rate of flow(i.e., the amount of external force applied to the spring) of thecontrast agent. In general, a spring with about 5-10 pounds of springforce is suitable.

A fluid flow restrictor may be manufactured from, include or becomprised of a needle, a short piece of tubing of narrow calibre (e.g.,an intravenous angiocatheter of 20 gauge or larger may be satisfactory),an orifice (for example made of ruby or sapphire), a focal compressionof the IV tubing, or other mechanism which impedes the flow of fluid.

It should be noted that a precision orifice may offer several advantageswhen employed as a fluid flow restrictor. For example, in thoseinstances where an incompressible fluid is to be administered, such asgadopentetate dimeglumine, gadoteridol, or gadodiamide, flow through anorifice is governed by the Bernoulli effect. In this regard, the flowrate of the fluid through the orifice is proportional to the square rootof the pressure drop:

${{{Infusion}\mspace{14mu}{Rate}} = {K*\sqrt{\left( \frac{F}{A} \right)}}}\mspace{11mu}$where:

-   -   K=a constant determined by the geometry of the orifice;    -   F=spring force; and    -   A=syringe cross-sectional area.

Further, it should be noted that the pressure drop across an orifice isgoverned by inertial effects of the fluid; the viscosity of the fluidhas little to no impact. As a result, an orifice minimizes the influenceof the viscosity of the fluid on the rate of flow of the fluid. Underthis circumstance, by using an orifice as a fluid flow restrictor, theBernoulli effect predicts the same flow rate regardless of temperatureof the fluid and regardless of which gadolinium compound is employed.Although in practice it is essentially impossible to entirely eliminateviscosity effects of the fluid, those effect are markedly reduced.

TABLE 1 provides the infusion rate, with respect to three MR contrastagents, for a variety of needles and flow restricting orifices whenemployed in an infusion device 12 substantially as illustrated in FIG.5A where the spring 40 is a 6 pound-force spring and the syringe 24 is a1 inch diameter, 50 cc syringe.

In those instances where the rate of flow of the fluid is dependent onthe ambient temperature or the temperature of the contrast agent,consistent operation of the infusion device 12 may require either atemperature controlled operating environment or use of a fluid flowrestrictor whose operational characteristics are essentially unaffectedby the viscosity of the fluid (e.g., a precision orifice).

With reference to FIG. 5B, in a preferred embodiment, the rateadjustment mechanism 50 is a manual type including a lever 50 a by whichthe user may increase or decrease the force applied to the plunger 24 a.The lever 50 a engages the plunger 24 a and spring 40 so that theresulting force applied to the plunger 24 a is essentially determined bythe sum of the force applied to the plunger 24 a (i.e., by the lever 50a) and the spring force, F. By employing this configuration, the usermay increase or decrease the rate of injection at a particular moment ofthe imaging sequence. For example, increasing the infusion rate at about10 to about 40 seconds prior to the acquisition of image datacorresponding to the center of the k-space would cause an elevated orrelatively high arterial gadolinium level to be maintained in the arteryof interest during acquisition of image data corresponding to the centerof k-space (typically it takes about 10-40 seconds for venous blood inthe arm to circulate through the heart and lungs to reach the artery ofinterest). Such a technique may provide additional contrast enhancementof the image of the artery relative to veins and surrounding tissue.

The infusion device 12 of FIG. 5B further includes a flow rate indicator52 to provide the operator an indication of a flow rate (injection rate)of the contrast agent to the patient. Here, the operator may visually oraudibly observe the rate of flow of the contrast agent to therebyaccurately control the rate of injection of the contrast agent into thepatient; the operator may customize or modify the contrast injectionrate.

The flow rate indicator may be implemented using an optical type sensorfor sensing the linear motion of, for example, the plunger 24 a, thespring 40, and/or the block and spring housing 30 a, or the rotationalmotion of the roller bearings 30 b. Such a mechanism permits an accuratemeasurement with little to no impact on the operation of the injectiondevice 12, including the motion of the plunger 24 a and the operation ofthe spring 40. That is, an optical type rate indicator has an advantageof not requiring physical contact with the contrast agent in the syringe24 or spring 40.

It is noted, however, that a fluid flow or motion sensor may also beemployed in the flow rate indicator 50. Such devices provide accurateinformation regarding the rate of flow of the contrast agent in thesyringe 24 or in the tubing 34 a.

As mentioned above, when the mechanical infusion device 12 is employedwithin the environment of the magnetic field, the materials used tofabricate the device 12 should be non-magnetic. That is, magneticmaterials should be avoided when the device 12 is implemented in or nearthe magnetic field of the magnetic resonance imaging apparatus. In thoseinstances, the spring 40 (FIGS. 5A and 5B) should be manufactured fromnon-magnetic materials, for example, eljaloy or inconel.

With reference to FIGS. 6A-C, the mechanical infusion device 12 may beimplemented using a bag-cassette configuration. The bag 46 contains acontrast agent. Analogous to the syringe configuration of FIGS. 5A and5B, the bag 46 may be placed into a cassette 48 which applies evenpressure over the contact surface of the bag 46. In operation, thecontrast agent then flows, similar to the syringe 24, from the bag,through the catheter 34 to the patient. As with the case with thesyringe configuration, fluid flow control is provided by means of afluid flow restrictor (i.e., the needle 34 b) used in combination with acassette 48 which provides the force.

It should be noted that the bag-cassette arrangement of FIGS. 6A-C mayemploy a saline drip apparatus 42 as well as a rate adjustment mechanism50. As with the syringe configuration, the rate of injection may beincreased or decreased using a manual, spring loaded, or pneumatic rateadjustment mechanism 50.

In some magnetic resonance suites, an opening exists in the walldividing the magnet of the imaging apparatus and the control equipment(i.e., computer and other electronic devices). In these situations,standard infusion pumps (containing metal, magnetized material andelectronic circuits) can be used from outside of the MR suite toimplement the methods described herein.

In one preferred embodiment, a pump manufactured by Abbott, the LifeCare 5000, may be implemented. The Life Care 5000 draws drugs (e.g.,contrast agent) directly from a bottle and preloads it into a longlength of tubing. The operating parameters of the Life Care 5000 may bepreprogrammed to execute numerous infusion rates.

In another preferred embodiment, the injection rate for contrast ismatched with the mapping of k-space so that a maximum or substantiallyelevated arterial gadolinium concentration correlates with acquisitionof image data corresponding to the center of k-space. That is, theoperating parameters of the pump may be pre-programmed to provide aninjection rate for contrast agent which is matched with the mapping ofk-space so that a maximum or substantially elevated rate of infusionoccurs about 10-40 seconds prior to the collection of image datacorresponding to the center of k-space.

This type of configuration offers several advantages including: (1) thecontrast agent (gadolinium) need not be removed from its shippingcontainers into an intermediate container, for example, a syringe; (2)the programmability of the pump allows variable injection ratesproviding for a maximum rate at the peak when the center of k-space isbeing mapped (which may be the most critical period during imageacquisition); (3) operator control of the operating parameters.

It should be noted that the Life Care 5000 Pump may not be ideallysuited for implementing all of the techniques described herein. Forexample, such deficiencies include the rates of injection of the pump,the degree of programmability of the flow delivery characteristics ofthe pump, and allowing the pump to administer contrast from multiplecontainers which will permit multiple 20 cc vials to be used.

As mentioned above, the present invention controls the precise timing ofthe injection of the paramagnetic contrast to provide preferentialenhancement of an artery of interest relative to adjacent veins andbackground tissue. The injection of the paramagnetic contrast agentshould temporally correlate to a period during which imaging data isbeing collected and preferably concurrent with the acquisition of imagedata. When implementing longer pulse sequences (greater than 2 minutes)or pulse sequences which collect image data representative of the centerof k-space some time after initiation of image data collection, it isimportant that no contrast be administered prior to magnetic resonancescan since the contrast may leak into the background tissues and cause adegradation of the image. If some paramagnetic contrast or othermagnetic resonance contrast has been administered prior to imaging, itis preferred to delay the arterial scan until this contrast has beenexcreted by the patient, in order to increase the probability ofobtaining the optimal images.

In those instances where the imaging apparatus employs pulse sequenceshaving very short data acquisition periods the contrast agent may beinjected before the initiation of collecting image data. Short pulsesequences may be characterized as those sequences for which the timerequired for contrast to circulate from injection site to the artery ofinterest becomes a significant fraction of the imaging time, forexample, data acquisition periods of less than 2 minutes. Under thiscircumstance, injection of the contrast agent before acquisition ofimage data is necessary to allow circulation of the contrast agent inthe patient and thereby correlate a maximum or substantially elevatedarterial concentration with the collection of image data representingthe center of k-space. Administering the contrast agent prior to theacquisition of image data would cause a relatively high arterialgadolinium level during the mapping of k-space. As discussed above, therelative timing between the administration of the contrast agent and thecollection of image data representing the center of k-space should beadapted to account for the injection mechanism employed, the location ofthe artery of interest, the size of the artery of interest, and thephysical condition of the patient. For example, the contrast may beadministered about 10-40 seconds before collection of image data toaccount for venous blood in the arm to circulate through the heart andlungs to reach the artery of interest. Thus, the amount of time beforeacquisition of image data may depend on the configuration of thecontrast delivery mechanism, the relative location of the artery ofinterest, the relative size of the artery of interest, and the conditionof the patient, including the age of the patient. Employing theseconsiderations in selecting and controlling the timing of the injectionprovide a more accurate alignment between the acquisition of datarepresentative of the center of k-space and a period of maximum orsubstantially elevated contrast concentration in the artery of interestrelative to adjacent veins.

In a preferred embodiment, a constant infusion should begin within a fewseconds of initiation of the scan process. The contrast infusion shouldend about 20 or more seconds before the completion of the scan; thisallows the intravenously injected contrast to circulate through theheart and into the arteries. A chaser of normal saline or other fluidmay be used to insure injection of the entire dose of the paramagneticcontrast (e.g., gadolinium) and, in addition, to insure that there issufficient venous return to propel the injected contrast to the heart.In a preferred embodiment, the contrast infusion rate is matched withthe mapping of k-space so that the maximum arterial gadoliniumconcentration occurs during acquisition of the center of k-space. Thismay permit injecting over a shorter period of time to achieve either ahigher injection rate or a lower contrast dose.

As discussed above, in order to adapt the timing of a maximum orsubstantially elevated rate of infusion and, in effect, a maximum orelevated arterial concentration of the contrast agent in the artery ofinterest, with the collection of image data corresponding to the k-spaceconsideration should be given to the impact of the contrast agentdelivery system or apparatus, the time interval for venous blood at thesite of infusion to reach the artery of interest, the size of the arteryof interest, and the location of the artery of interest has on thiscorrelation. Each of these “variables” impact on the time between themaximum or elevated rate of injection and when a maximum or elevatedarterial concentration in the artery of interest is observed.

The inherent delay in the contrast delivery system depends on, forexample, the length of the tubing 14, between the infusion device 12 andthe patient. Such a delay, once measured or determined, may beconsidered a “constant” for a given delivery or infusion apparatus.

The time interval for venous blood at the site of infusion to reach theartery of interest (i.e., the “circulation time”) depends on thelocation of the artery of interest and the physical condition of thepatient. Typically, this time interval may vary from about 10 to about30 seconds. The time interval may be longer if the artery of interest isfar from the heart, for example, in the foot, or if the site of infusionis a peripheral vein such as in the hand.

Further, young, healthy patients with normal cardiac output tend to havea faster flow and a short circulation time, between 10-20 seconds(typically about 15 seconds). Older patients and patients with lowcardiac output have a slower circulation times, between 20-30 seconds ormore. The circulation time will also be longer for an IV in the handcompared to one in the upper arm. Central lines which inject directlyinto the SVC or right atrium will have the shortest circulation times.

In another preferred embodiment, the period of a maximum orsubstantially elevated rate of infusion of the magnetic resonancecontrast agent to the patient is adapted according to the size of theartery of interest to correlate with the period of the collection ofimage data corresponding to the center of k-space. In this regard, wherethe artery of interest is relatively large (e.g., the aorta), a periodof a substantially elevated or maximum injection rate may overlap for asmaller fraction of the period of collecting image data representativeof the center of k-space than where the artery is relatively small(e.g., renal). For example, when imaging larger arteries, theadministration of the contrast agent may include a period of asubstantially elevated or maximum rate of contrast which provides asubstantially elevated or maximum arterial concentration for less than50% of the period during which the system collects image datacorresponding to the center of k-space; and preferably between 20% to50%. Where the artery of interest is relatively small, it is preferablethat a period of maximum or substantially elevated rate of injectionprovide a maximum or substantially elevated concentration of thecontrast in the artery of interest for more than 50% of the period ofmapping the center of k-space; and preferably between 50% to 85%.

With reference to FIG. 7, the infusion of the magnetic resonancecontrast agent may be by way of manual means. In this embodiment, asyringe 20, having needle 22, is coupled to a vessel 14 containing themagnetic resonance contrast agent. The vessel 14 is coupled to thepatient using conventional techniques, for example, appropriatelyselected tubing 14 which permits fluid flow between the vessel 18 andthe patient, for example, an angiocatheter.

When implementing the present invention via manual injection, i.e.,injecting the magnetic resonance contrast agent by hand, in a preferredembodiment, the infusion “path” includes a fluid flow restrictor whichadds resistance to the flow of gadolinium during administration into thebody. It should be noted that a fluid flow restrictor may be, forexample, a standard injection needle or small calibre angiocatheter. InFIG. 7, the fluid flow restrictor may be the needle 22 of syringe 20and/or the angiocatheter 14. Use of small needles, short pieces oftubing of narrow calibre, an orifice, and/or small calibreangiocatheters may alleviate errors of injecting the contrast toorapidly and, as a result, depleting or running-out of contrast beforecompletion of the scan or improperly correlating a maximum or elevatedrate of infusion with the mapping of k-space. In a preferred embodiment,the needle size may be 22 gauge or smaller diameter (higher than orequal to 22 gauge) depending upon the viscosity of the contrast agent.

It may be convenient to preload the contrast into a vessel or length oftubing with luer lock or other appropriate connectors at each end of thetubing. It is then possible to use a single saline filled syringe toinject the contrast followed by a saline chaser without having to switchsyringes or pumps. Saline is a preferred fluid to use as a chaser sinceit can be made isotonic with blood and is compatible with mostintravenous fluids and pharmaceuticals that may already be flowingthrough a patient's IV line.

In a preferred embodiment, the contrast is infused slowly at thebeginning and fastest in the middle of the acquisition. This type ofinjection pattern, based upon the fact that the contrast does somewhatcontribute to venous and background tissue enhancement, avoids excessivecontrast early in the acquisition.

Post-Processing

Post-processing of the scan data may be used. Maximum intensityprojection (MIP) collapse images are useful for rapidly examining theentire arterial circulation within the region of interest. It may beuseful to reformat and selectively collapse the data through thespecific arteries of interest. Additional contrast may be obtained bydigitally subtracting a pre-gadolinium acquisition from the dynamicgadolinium acquisition. Volume rendering may also be useful and ispossible with high contrast volume data sets.

Immediately below are examples of results obtained from use of preferredembodiments of the present invention. The parameters of the examples aredetailed therein.

EXAMPLE 1

Contrast between peripheral arteries and veins in images obtained byimaging dynamically during the administration of gadopentetatedimeglumine was investigated in sixteen patients referred foraorta-iliac magnetic resonance arteriography. These included 9 males and7 females with a mean age of 72 ranging from 67 to 83. The indicationsfor the study included hypertension (6), abdominal aortic aneurysm (AAA,6) claudication (4) and renal failure (9). Some patients had more thanone indication.

Parameters

All imaging was performed on a 1.5 Tesla superconducting magnet (GeneralElectric Medical Systems, Milwaukee, Wis.) using the body coil andversion 4.7 software. A 3D FT, coronal, spoiled, gradient echo volumewas acquired centered on the mid-abdomen. The imaging parametersincluded: 12 cm volume with 60 partitions, 2 mm partition thickness, TRof 25 msec, a TE of 6.9 msec, a flip angle of 400, first order flowcompensation, 36 centimeters field of view, 256 by 192 matrix. Theimaging time was 5 minutes and 10 seconds. Frequency was set superior toinferior so that phase artifact from diaphragmatic and cardiac motionwould not superimpose on the abdominal aorta and IVC. When possible,phase artifact noise was minimized by excluding the heart and lungsentirely from the field of view. No saturation pulses were employed. Thevolume data were reformatted through vessels of interest and alsodisplayed as maximum intensity projections.

Gadopentetate Dimeglumine Injection

After pre-scanning, venous access was obtained via a 22 gaugeangiocatheter. A dynamic acquisition was then performed during handinjection of gadopentetate dimeglumine (Berlex Laboratories, CedarKnoll, N.J.), 0.2 millimoles/kilogram. The injection was initiatedwithin 5 seconds of initiating the image acquisition. The injection ratewas constant (within the limitations of a hand injection) and timed tolast until 10-20 seconds before completion of the scan. The injectionincluded a 5 cc normal saline chaser to ensure injection of the entiregadopentetate dimeglumine dose. As a result, the gadopentetatedimeglumine ended approximately 30-40 seconds before completion of thescan and the saline chaser ended about 10-20 seconds before completionof the scan. In order to compare to the conventional, non-dynamic,gadolinium-enhanced MRA, a second, identical acquisition was thenacquired without altering the imaging or prescan parameters.

Signal Measurements

Signal intensity was measured in the abdominal aorta, IVC, iliac arteryand vein, renal artery and vein, celiac trunk, SMA, portal vein, hepaticvein and background tissue (including fat, skeletal muscle, kidney,liver and spleen) for 7 regions of interest per measurement. As many ofthese measurements as possible were obtained from the central 20partitions and all measurements were obtained from the central 40partitions. Identical regions of interest were used to compare vesselson the dynamic and post-gadolinium images. The standard deviation of theaorta signal was recorded as noise. Differences in the aorta and IVCsignal-to-noise ratio were evaluated for each patient as well as for themeans of all patients with Students t-test. In addition, thesignificance of differences in the mean portal vein, hepatic vein, renalvein and iliac vein signal compared to the IVC were evaluated withStudents t-test. The presence of aneurysms, occlusions and stenoses(>50%) was noted on the individual dynamic images and on maximumintensity projections and compared to findings at surgery orarteriography when available.

Results

All sixteen patients tolerated the imaging and gadopentetate dimegluminewell; there were no complications. FIGS. 8A-C illustrate the typicalimages obtained before, during and after injection of gadopentetatedimeglumine, respectively. Before the injection, the vessels wereheavily saturated with only a few streaks of vessels visible at theedges of the 3D volume. Images obtained during injection showedenhancement of the arteries while the IVC remained indistinguishablefrom the background tissue. Aorta IVC signal intensity ratios, shown inTABLE 2, confirmed this preferential arterial enhancement in everypatient studied. Images obtained after the injection was completeddemonstrated comparable enhancement of both arteries and veins.

It should be noted that with dynamic imaging there is bright arterial aswell as portal vein and splenic vein enhancement but no visible IVC oriliac vein enhancement and no in-plane saturation. Post gadopentetatedimeglumine images show comparable enhancement of both arteries andveins.

TABLE 3 provides the average signal intensity for all tissues studiedfor both the dynamic and post-injection sequences. With dynamicgadopentetate dimeglumine the average aorta signal-to-noise ratio was10±0.9 compared to 5.1±1.4 in the IVC (p value≦0.0001), while postgadopentetate dimeglumine the aorta and IVC were nearly identical,10±1.4 and 9.5±1.3 respectively. Although all veins were less brightthan the aorta on the dynamic images compared to post gadopentetatedimeglumine images, there were variations among the veins analyzed. Theiliac vein was the least enhanced, 4.7±1.6, while the portal vein wasthe brightest, 8.3±1.6 followed by the hepatic, 7.5±2.1, and renal,6.2±1.8, veins; these differences were significant to the p<0.01 levelcompared to the mean IVC signal-to-noise ratio.

Angiographic and/or surgical correlation was available in 6 of the 16patients. In the vascular segments for which definitive correlation wasavailable, magnetic resonance arteriography correctly identified 2occlusions (1 common iliac and 1 renal artery), 10 stenoses (4 renalartery, 2 iliac artery, 2 distal aorta, 1 inferior mesenteric artery and1 celiac) and 6 aneurysms (3 aortic and 3 iliac artery). There was noevidence of arterial in-plane saturation in any patient. In one patientwith a common iliac artery occlusion, there was no difficultyvisualizing reconstituted flow distal to the occlusion.

TABLE 4 reveals an apparent trend for patients with a history of cardiacdisease, claudication or aneurysms to have the greatest aorta/IVC signalintensity ratio. The sample size may have been too small to establishstatistically significant correlations. Further, one patient withcardiac disease, aneurysmal disease and claudication had the highestaorta/IVC signal intensity ratio. These trends are opposite fromtime-of-flight imaging where cardiac disease and aneurysms areassociated with image degradation.

EXAMPLE 2

In order to determine the optimal timing of contrast administration, twomethods of dynamic administration, bolus and continuous infusion, werecompared to non-dynamic injections and to conventional time-of-flightimaging.

Gadolinium enhanced magnetic resonance arteriography was performed in 52patients referred for routine MRA of the abdominal aorta or branchvessels. Imaging was performed as described in Example 1. The totalacquisition time was 5:08 minutes to cover approximately 36 cm of aortaand iliac artery in the superior to inferior dimension. In 20 of thepatients of the dynamic gadolinium infusion imaging was performed with28 partitions each 2 mm thick with a 256 by 256 matrix to reduce thescan time to 3:18 minutes.

After pre-scanning, venous access was obtained via a 22 gaugeangiocatheter. A dynamic acquisition was then performed during handinjection of gadolinium dimeglumine (Berlex Laboratories, Cedar Knoll,N.J.) 0.2 millimoles/Kg. In 12 patients, the injection was given as abolus. The bolus was begun within 5 seconds of starting the acquisitionand completed within the first 1 to 2 minutes of the 5 minute scan. Inthe other 40 patients, an injection of the same dose was carefully timedto be constant and continuous over the entire period of imagingbeginning within 5 seconds of commencing the acquisition and ending 20seconds before the end of the acquisition. In all patients, a 5 ccnormal saline chaser was given to ensure injection of the entiregadopentetate dimeglumine dose.

For comparison purposes, 16 of these patients were imaged with anidentical acquisition after the dynamic infusion without altering theimaging or prescan parameters. Also, for comparison, axial 2D andmultiple overlapping 3D (MOTSA) time-of-flight images were acquiredprior to the gadolinium injection. Inferior pre-saturation pulses wereused with the time-of-flight sequences to suppress venous in-flow.

Signal intensity was measured in all patients in the aorta, IVC andbackground tissues (fat and skeletal muscle) for at least 3 regions ofinterest per measurement for all sequences. The signal's standarddeviation within the aorta was recorded as noise.

Images obtained dynamically, during steady infusion of gadopentetatedimeglumine, showed sufficient arterial enhancement to clearly definethe aorta and branch vessel anatomy while the IVC and iliac veinsremained indistinguishable from the background tissues. The portal veinis visible but is not as bright as the aorta. Images obtainednon-dynamically, after the injection was completed, or with a dynamicbolus injection demonstrated comparable enhancements of both arteriesand veins.

The observation of significant, preferential arterial enhancement with acontinuous dynamic contrast infusion was confirmed by region of interestanalysis (see TABLE 5 and FIG. 9). The ratio of aorta to IVC signalintensity for the 5 minute infusion, 2.0±0.5, was significantly higherthan for non-dynamic imaging 1.1±0.1 (p<0.001) or for the dynamic bolus1.2±0.2 (p<0.001). Even better differentiation between the aorta and IVCwas obtained by injecting the same dose of gadopentetate dimegluminemore quickly over a 3:18 minute acquisition. Although this aorta-to-IVCsignal intensity ratio was not as favorable as for 2D time-of-flight orMOTSA imaging, it was adequate in all cases for clearly distinguishingthe aorta and abdominal aorta branch vessels from the IVC and iliacveins.

Dynamic contrast enhanced 3D imaging had no saturation, pulsatility ormisregistration artifacts. Even in aneurysms, which tend to havestagnant and/or turbulent flow, there was no loss of signal. Bycomparison, every 2D time-of-flight study had pulsatility artifacts andsome had misregistration and/or in-plane saturation artifacts. The MOTSAimages had no pulsatility or misregistration artifacts but every MOTSAstudy showed some degree of arterial saturation and they wereparticularly degraded in aneurysmal segments.

Administering gadopentetate dimeglumine dynamically as a steady,continuous, infusion for the entire period of a 3D FT acquisition, at adose of 0.2 millimoles/Kg, gives sufficient preferential arterialenhancement to visualize arteries distinctly from veins and backgroundtissues regardless of the magnitude or direction of flow. The importanceof injecting dynamically and continuously during the entire scan isillustrated by the absence of significant preferential enhancement whenthe contrast is administered non-dynamically or as a dynamic bolus.Images obtained at a lower dose, 0.1 millimole/Kg, were not useful.

Since dynamic gadolinium enhanced MRA does not depend upon the in-flowof unsaturated spins, it eliminates some of the saturation problems thatcomplicate routine time-of-flight imaging. The imaging volume can beoriented in any plane for optimal coverage of the vessels of interestwithout concern for saturation. In these patients, in-plane, coronalimaging of the aorta-iliac system reduced the image acquisition time by5 to 20 fold over 2D time-of-flight and MOTSA imaging and had superiorresolution and superior aorta signal-to-noise ratios.

A 3D FT acquisition was used in this example partly because of itsintrinsically high spatial resolution and high signal-to-noise and alsobecause its main limitation, arterial saturation, is eliminated by thegadolinium. The TE was chosen to be as short as possible at a valuewhere fat and water protons are out of phase. A short TE helps tominimize motion related phase artifacts. Having fat and water out ofphase provides an element of fat suppression which improvesartery-to-background contrast since fat is the brightest backgroundtissue.

EXAMPLE 3

MRA image data for a patient presenting with an abdominal aorticaneurysm was acquired as described in Example 1. MRA images are shown inFIGS. 10A and 10B.

The MRA of FIG. 10A depicts the aneurysmal aorta and aneurysmal commoniliac arteries as well as severe stenoses of the right external iliac(curved arrow) and inferior mesenteric (straight arrow) arteries and amild stenosis of the left common iliac artery. The internal iliacarteries are excluded because of their posterior course. FIG. 10Billustrates a digital subtraction angiogram which confirms the findingsin FIG. 10A as discussed immediately above.

EXAMPLE 4

A pump (as illustrated in FIG. 5A) was loaded with a 50 cc syringecontaining 42 cc of gadodiamide. A 23 gauge butterfly was attached tothe end of the syringe with its standard luer-lock connector and pluggedinto a side port of the patient's intravenous (IV) line within a fewfeet of the IV skin entry site. The pump was located approximately 15 cmor more away from the imaged volume.

Usually the IV site was in the forearm or antecubital fossa. A plasticKelly clamp on the butterfly tubing prevented premature gadoliniuminfusion. The gadolinium infusion was begun simultaneous with beginningthe image acquisition by releasing the clamp on the butterfly tubing.This combination of 6 pounds spring force and a ⅝ inch, 23 gaugebutterfly needle gave an infusion rate of 18 cc/minute which wasslightly reduced by the additional resistance of the IV tubing andangiocatheter. For the 42 cc volume of gadolinium, the calculatedinfusion time was 2:20 minutes. This was shortened by manuallyincreasing the rate of injection during the middle of the acquisitionsuch that the maximum arterial concentration occurred during acquisitionof the center of k-space.

The pump infusion finished with one minute of scan time remaining.Residual gadolinium within the IV tubing (about 4 cc) was flushedthrough with saline to ensure delivery of the entire dose.

The procedure of EXAMPLE 4 produced excellent quality MRA images ofarteries without the confounding effects of excessive venousenhancement.

Various preferred embodiments of the present invention have beendescribed. It is understood, however, that changes, modifications andpermutations can be made without departing from the true scope andspirit of the present invention as defined by the following claims,which are to be interpreted in view of the foregoing.

For example, the correlation techniques for adapting the timing of amaximum or elevated rate of infusion and the collection of image datarepresentative of the center of k-space may be used in variouscombinations according to the particulars of the contrast deliverysystem, the artery of interest, the location of the artery of interest,the size of the artery of interest, the condition of the patient, andthe type of pulse sequence employed by the imaging apparatus. Adaptingthe timing of a maximum or elevated rate of infusion to correlate withthe collection of image data representative of the center of k-spaceinsures that such data will be collected over some period during which amaximum or elevated contrast concentration is realized in the artery ofinterest.

TABLE 1 Infusion Rates of Gadolinium Chelates at 24° C. Gd-DTPAGadoteridol Gadodiamide Viscosity @ 20° C. [cP]* 4.9 2.0 2.0 FlowRestrictor Infusion Rate Size Gd-DTPA Gadoteridol Gadodiamide NeedlesBD ® 18 g  1.5″ 100 126 120 Terumo ® 20 g  1.5″ 44 66 64 Terumo ® 21 g 1.5″ 27 47 44 Terumo ® 22 g  1.5″ 15 29 23 Terumo ® 23 g   1″ <4 <4 <4Butterflies ABBOTT ® 21 g  .75″ 21 37 36 ABBOTT ® 23 g  .75″ 8 19 18ABBOTT ® 25 g .375″ <4 8 7.3 Orifice 0.010″ 21 25 25 *Values provided bymanufacturer (Nycomed)

TABLE 2 Aorta/IVC Signal Intensity Ratios for Dynamic 3D Imaging PatientPrimary heart Signal Intensity During Injection #-sex Age Indicationdisease creatinine Aorta IVC ratio** p value  I-m 83 AAA yes* 2 7.9 ±1.0 3.9 ± 0.6 2.0 <.0001  2-f 73 hypertension yes* 8  11 ± 1.0 8.2 ± 1.31.4 .0002  3-m 73 claudication yes 2.2  10 ± 2.0 3.7 ± 0.5 2.8 .0003 4-f 67 hypertension no .9  10 ± 0.4 5.1 ± 0.6 2.0 <.0001  5-f 70hypertension yes* 3 8.9 ± 0.9 4.5 ± 0.4 2.0 <.0001  6-m 67 renal failureyes 6  11 ± 0.5 4.9 ± 0.4 2.2 <.0001  7-f 80 AAA yes 1.8  10 ± 0.4 5.9 ±0.5 1.8 <.0001  8-f 76 renal failure yes* 3.6 9.1 ± 0.6 5.0 ± 0.6 1.8<.0001  9-m 68 AAA no 1  11 ± 0.5 7.2 ± 0.3 1.4 <.0001 10-m 70claudication yes 1.2  11 ± 0.5 5.4 ± 0.3 2.0 <.0001 11-m 74 hypertensionno 1 8.9 ± 0.3 6.0 ± 0.3 1.5 <.0001 12-m 80 hypertension yes* 3.2  10 ±0.4 3.8 ± 0.9 2.6 <.0001 13-m 74 AAA yes 4 9.8 ± 1.0 3.7 ± 0.8 2.6<.0001 14-f 67 AAA no 1  10 ± 0.3 5.9 ± 0.6 1.8 <.0001 15-m 67hypertension no 1.5  11 ± 0.9 4.6 ± 0.9 2.4 <.0001 16-f 71 claudicationyes* 6  11 ± 1.3 3.1 ± 0.6 3.5 <.0001 AVERAGE  10 ± 0.9 5.1 ± 1.4 2.0<0.0001 *cardiac disease with history of CHF **Aorta/IVC signalintensity ratio

TABLE 3 Average Signal-To-Noise Ratios During and Post GadopentetateDimeglumine Injection Dynamic Post Ratio Injection InjectionDynamic/Post ARTERIES Aorta  10 ± 0.9  10 ± 1.4 1.0 Iliac Artery 9.8 ±1.3  10 ± 1.3 .98 Renal Artery 9.7 ± 1.9  10 ± 2.5 .99 Celiac & SMA  10± 1.7  11 ± 1.8 .91 VEINS IVC 5.1 ± 1.4 9.5 ± 1.3** .54 Iliac Vein 4.7 ±1.6* 9.2 ± 1.3** .51 Renal Vein 6.2 ± 1.8* 9.1 ± 1.9** .68 Hepatic Vein7.5 ± 2.1* 8.3 ± 1.0** .90 Portal Vein 8.3 ± 1.6* 9.0 ± 3.3** .92BACKGROUND Kidney 7.3 ± 1.0 8.3 ± 1.0 .88 Liver 5.3 ± 0.6 5.8 ± 1.8 .91Spleen 5.9 ± 2.3 6.3 ± 2.3 1.1 Fat 4.3 ± 0.7 4.0 ± 0.8 1.1 Muscle 2.4 ±0.5 3.2 ± 0.7 .75 *p > 0.01 compared to IVC signal intensity **p > 0.01compared to signal intensity for dynamic injection ***standard deviationof signal in the space outside the patient

TABLE 4 Effect of Cardiac Disease, Claudication and Aneurysms onAorta/IVC Signal Intensity Ratio Subgroup # of Patients Aorta/IVC* pvalue Cardiac Disease 12 2.2 ± 0.6 0.08 No Cardiac Disease 4 1.8 ± 0.40.08 Claudication 4 2.6 ± 0.8 0.12 No Claudication 12 2.0 ± 0.4 0.12Aneurysm 7 2.2 ± 0.7 0.32 No Aneurysm 9 2.0 ± 0.5 0.32 *Signal IntensityRatio

TABLE 5 Effect of Injection Method on Aorta Signal-to-Noise andContrast-to-Noise Ratios Image Contrast time/cm Voxel Aorta- Aorta-Pulse Injection # of (sec/ Volume Saturation Pulsatility Aorta Aorta/IVCIVC Aorta-fat muscle Sequence Method patients cm) (mm³) ArtifactsArtifacts SNR SI ratio CNR CNR CNR 2D TOF No gado 11 40 6.0 yes yes 8.2± 2.8 3.7 ± 1   5.8 ± 1.9 5.5 ± 2   6.8 ± 2.4 MOTSA No gado 12 92 4.7yes no 8.9 ± 2.5 2.7 ± 0.9 5.1 ± 1.8 4.9 ± 1.7 6.3 ± 1.9 Gado: 3Dnon-dynamic 16 9 3.1 no no   9 ± 2.0 1.1 ± 0.1 0.6 ± 0.5 5.4 ± 1.5 6.2 ±1.9 Gado: 3D bolus* 12 9 3.1 no no  12 ± 2.4 1.2 ± 0.2 2.7 ± 1.4 7.5 ±1.6 9.1 ± 1.9 Gado: 3D infusion**¹ 20 9 3.1 no no  10 ± 1.2 2.0 ± 0.54.7 ± 1.4 5.4 ± 1.1 7.3 ± 1.1 Gado: 3D infusion**² 20 5.5 3.1 no no 10 ±2  2.4 ± 0.8 5.6 ± 1.7 6.8 ± 1.9 8.2 ± 1.7 SNR = signal-to-noise ratioCNR = contrast-to-noise ratio *gadopentetate dimeglumine givendynamically as a bolus within the first 2 minutes of the acquisition.**gadopentetate dimeglumine given dynamically as a constant infusionspread over the entire acquisition. ¹5 minutes ²3 minutes

1. A method of imaging an artery in a patient using magnetic resonanceimaging and an administered magnetic resonance contrast agent,comprising, collecting image data of an image sequence wherein the imagesequence includes: image data which is representative of a center ofk-space, and image data which is representative of a periphery ofk-space, and wherein the image sequence is arranged to collect imagedata which is representative of the periphery of k-space beforecollecting image data which is representative of the center of k-space;and temporally correlating the administration of the magnetic resonancecontrast agent to the patient with collecting image data which isrepresentative of the center of k-space based on an estimatedcirculation time of the contrast agent in the patient.
 2. The method ofclaim 1 wherein temporally correlating the administration of themagnetic resonance contrast agent to the patient with collecting imagedata which is representative of the center of k-space further includestemporally correlating the administration of the magnetic resonancecontrast agent to the patient based on the delay time in a deliverysystem.
 3. The method of claim 1 wherein temporally correlatingadministering the magnetic resonance contrast agent with collectingimage data based on the circulation time of the contrast agent providesa concentration of contrast agent in the artery is substantially greaterthan a concentration of contrast agent in veins and background tissueadjacent to the artery while collecting the image data which isrepresentative of the center of k-space.
 4. The method of claim 1wherein the image sequence is a 3D pulse sequence.
 5. The method ofclaim 4 wherein the artery is the aorta and the image data correspondingto the aorta is reconstructed to create a maximum intensity projection.6. The method of claim 1 wherein temporally correlating theadministration of the magnetic resonance contrast agent to the patientwith collecting image data which is representative of the center ofk-space further includes temporally correlating based on a location orsize of the artery.
 7. The method of claim 1 wherein the imaging pulsesequence is arranged to collect image data which is representative ofthe periphery of k-space before and after collecting image data which isrepresentative of the center of k-space.
 8. The method of claim 1wherein the imaging sequence is a 3D pulse sequence having a repetitiontime (TRI that is less than 25 milliseconds.
 9. A method of imaging anartery in a patient using a magnetic resonance imaging apparatus,comprising, administering a magnetic resonance contrast agent to thepatient; collecting image data of an imaging pulse sequence; andtemporally correlating administering the magnetic resonance contrastagent with collecting image data based on the type of the imaging pulsesequence and the circulation time of the magnetic resonance contrastagent in the patient to provide a concentration of the contrast agent inthe artery which is substantially greater than the concentration ofcontrast agent in veins adjacent to the artery during collecting theimage data.
 10. The method of claim 9 wherein the imaging pulse sequenceis arranged to collect image data which is representative of a peripheryof k-space before and after collecting image data which isrepresentative of a center of k-space.
 11. The method of claim 9 whereinthe pulse sequence is arranged to collect image data which isrepresentative of the center of k-space before collecting image datawhich is representative of the periphery of k-space.
 12. The method ofclaim 9 wherein temporally correlating administering the magneticresonance contrast agent with collecting image data further includescorrelating administering the magnetic resonance contrast agent withcollecting the image data based on the amount of contrast agentadministered.
 13. The method of claim 9 further including instructingthe patient to suspend respiration while collecting the image data whichis representative of a center of k-space.
 14. The method of claim 9wherein temporally correlating administering the magnetic resonancecontrast agent with collecting image data further includes administeringthe magnetic resonance contrast agent to the patient before collectingimage data to provide a maximum concentration of the contrast agent inthe artery relative to the veins adjacent to the artery to coincide withcollecting the image data which is representative of a center ofk-space.
 15. The method of claim 9 wherein the imaging sequence is a 3Dpulse sequence having a TR that is less than 25 milliseconds.
 16. Themethod of claim 15 wherein the 3D pulse sequence is arranged to collectthe image data which is representative of the center of k-spacesubstantially at the beginning of the 3D pulse sequence.
 17. The methodof claim 16 wherein administering the magnetic resonance contrast agentincludes administering the contrast agent to the patient by bolusinjection.
 18. The method of claim 15 wherein the 3D pulse sequence isarranged to collect the image data which is representative of the centerof k-space substantially in the middle of the 3D pulse sequence.
 19. Themethod of claim 9 wherein the artery is the aorta and the image datacorresponding to the aorta is reconstructed to create a maximumintensity projection.